(Na++K+)-ATPase is a target receptor for digitalis and related drugs. Digitalis, digoxin, ouabain and related substances are cardiac glycosides derived from plants. The main pharmacodynamic property of cardiac glycosides is the ability to increase the force of myocardial contraction in a dose-dependent manner (positive inotropic effect). The most probable explanation for the direct positive inotropic effect is the ability of cardiac glycosides to inhibit membrane-bound (Na++K+)-activated adenosine triphosphatase [(Na++K+)-ATPase] (Hoffman, B. F. and J. T. Bigger, Jr., “Digitalis and Allied Cardiac Glycosides” in The Pharmacological Basis of Therapeutics, eds. Goodman and Gilman, p. 732, (1980)). The hydrolysis of adenosine triphosphate (ATP) by this enzyme provides the energy for the sodium potassium pump.
Many researchers have tried to isolate a specific endogenous inhibitor of plasma membrane Na+, K+-ATPase similar to digitalis or ouabain, but of mammalian origin, by measuring immunoreactivity in plasma, to the digoxin radioimmunoassay in situations where the inhibitor might be elevated. The definitive structure of plasma, urinary or tissue inhibitor of Na+, K+-ATPase is not known (Haupert, G. T., Jr., in The Na+, K+-Pump, Part B: Cellular Aspects; Skou, J. C., et al., Eds., p. 297-320 (1988)).
The precise structural region of (Na++K+)-ATPase that regulates cardiac function is unknown. Hence, relatively little is known about the endogenous regulation of (Na++K+)-ATPase. Catecholamines (Phillis, J. W., Cell, Tissue and Organ Cultures in Neurobiology, pp. 93-97 (1978); Horwitz, B. A., Fed. Proc., 38:2170-2176 (1979)), thyroid hormone (Smith, T. J. and I. S. Edelman, Fed. Proc., 38:2150-2153 (1979)), aldosterone (Rossier, B. C., et al., Science, 12:483-487 (1987)), linoleic and linolenic acids (Bidard, J. N., et al., Biochem. Biophys. Acta., 769:245 (1984); Tamura, M., et al., J. Biol. Chem., 260:9672 (1985); and vanadium (Cantley, L. C., Jr., et al., J. Biol. Chem., 243:7361-7368 (1978)) have all been linked to either direct or indirect effects on enzyme activity.
Because of their positive inotropic effect, cardiac glycosides (e.g., digitalis and ouabain) are unrivaled in value for the treatment of heart failure. Cardiac glycosides are most frequently used therapeutically to increase the adequacy of the circulation in patients with congestive heart failure and to slow the ventricular rate in the presence of atrial fibrillation and flutter.
However, cardiac glycosides have narrow therapeutic indices and their use is frequently accompanied by toxic effects that can be severe or lethal. The most important toxic effects, in terms of risk to the patient, are those that involve the heart (e.g., abnormalities of cardiac rhythm and disturbances of atrio-ventricular conduction). Gastrointestinal disorders, neurological effects, anorexia, blurred vision, nausea and vomiting are other common cardiac glycoside-induced reactions. Consequently, there is a need in the art for positive inotropic agents which overcome the disadvantages associated with known agents, as well as a need for further information on the mechanisms and receptors associated with cardiac muscle contractility.
It would be highly beneficial to provide patients with a therapeutic composition wherein the cardiac regulatory functions of (Na++K+)-ATPase are specifically regulated. Moreover, the identification of the key structural regions and amino acids of the (Na++K+)-ATPase would be of great importance in developing more specific therapeutic molecules, which specifically regulate the cardiac function and differ in characteristics from currently available digitalis glycosides.